Mechanochemistry‑Enabled One‑Pot Formation of 1,2,4‑Triazoles toward the Sustainable Penipanoid A Synthesis

Abstract

Mechanochemistry has emerged as a transformative innovation in chemical synthesis, enabling solvent-free, energy‑efficient transformations that align with the principles of green chemistry. Herein, we report a sequential two‑step, one‑pot ball‑milling protocol for the synthesis of 1,3,5‑trisubstituted 1,2,4‑triazoles, expanding the scope of nitrogen heterocycle chemistry into the mechanochemical domain. N-aroyl and acyl amidines were prepared quantitatively from benzamides, heteroaryl carboxamides, and alkyl carboxamides using 1,1‑dimethoxy‑N,N‑dimethylmethan or ethanamine (DMF‑DMA or DMA-DMA), or Bredereck’s reagent (tert‑butoxy bis(dimethylamino)methane) under solvent-free milling conditions, followed by condensation with hydrazines in the presence of acetic acid to afford triazoles in good to excellent yields (51–91%). The methodology demonstrated broad substrate tolerance, including aryl, heteroaryl, and alkyl derivatives, and was successfully applied to the sustainable synthesis of penipanoid A, a bioactive marine natural product, under mild, solvent‑free conditions.